Lung cancer is the most common cause of cancer related deaths in both men and women in the United States. The majority of patients (80%) will have non-small cell lung cancer (NSCLC) and will present with advanced stage lung cancer which is incurable with currently available therapies. For patients with advanced NSCLC, chemotherapy is mainstay of treatment and is associated with a median survival of 8-10 months. These figures have changed very little in the last 25 years. An important research goal has been to understand critical molecular alterations in NSCLC which may lead to the identification of effective therapies for NSCLC patients. A compelling example of this approach was the discovery of somatic mutations in the epidermal growth factor receptor (EGFR) and their association with dramatic clinical benefits in patients with EGFR mutant NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs). EGFR TKIs have been shown to be effective therapeutic agents for patients with non-small cell lung cancer (NSCLC) with tumors that harbor somatic activating mutations in EGFR. In a phase III clinical trial chemotherapy naove NSCLC patients with EGFR mutations had a significantly longer progression free survival when treated with an EGFR TKI than with conventional chemotherapy. As EGFR mutations are only found in 10-15% of all NSCLC patients, it is imperative to identify other subsets of NSCLC patients whose tumors may contain activated oncogenes and to develop effective therapies for these patient subsets. The fusion of the anaplastic lymphoma kinase (ALK) with the echinoderm microtubule-associated protein-like 4 (EML4) has been detected in 2-7% of Caucasian and Asian NSCLC and EML4-ALK fusion genes are transforming both in vitro and in vivo models. Although translocations involving ALK in cancer have been recognized for 15 years, specific ALK kinase inhibitors are only recently being developed and are entering early stage clinical studies. Thus it will be critical to identify the most effective ALK kinase inhibitor and to determine whether such inhibitors are effective in NSCLC models harbouring EML4-ALK and to understand the key signalling pathways associated with their efficacy and resistance. These studies have enormous implications for NSCLC patients with EML4-ALK containing tumors as analogous to EGFR mutant NSCLC, ALK kinase inhibitors may be effective therapies for this subset of NSCLC patients. Recently numerous activating point mutations in the ALK kinase domain have been discovered in neuroblastoma - the most common neural tumor of children. Thus ALK kinase inhibitors may be a good therapeutic approach in a wide variety of malignancies. These studies will be accomplished through the following specific aims: Aim 1: To establish the efficacy of various ALK kinase inhibitors in NSCLC models with different EML4-ALK fusion genes. Aim 2: To synthesize highly potent and specific ALK kinase inhibitors. Aim 3: T determine mechanisms of resistance to ALK kinase inhibitors. PUBLIC HEALTH RELEVANCE: Lung cancer is the most common cause of cancer related deaths in both men and women in the United States. The majority of patients (80%) will have non-small cell lung cancer (NSCLC) and will present with advanced stage lung cancer which is incurable with currently available therapies. The overall goal of this research is to better understand critical molecular alterations in NSCLC which may lead to the identification of more effective therapies for NSCLC patients.